1. Field of the Invention
The present invention pertains to novel long-acting analgesics, prophylactic or rescue agents in the treatment of opiate drug abuse and a new class of antiobesity drugs. In particular, the invention is directed to O-aryl or O-aralkyl ethers of oxymorphone, naltrexone and naloxone derived oximes, their pharmaceutically acceptable salts and to the methods of synthesizing the same.
2. Description of the Prior Art
The evidence for multiplicity of opioid receptor subtypes in the prior art lead to the discovery of novel selective agonists and antagonists as reported in Lever et al. Ann. Rep. Med. Chem., 18, 51 (1983). The discovery of a potent, selective agonist or antagonist reduces or eliminates the side effects associated with a nonselective compound. Increased potency and selectivity of the agonist and antagonist compounds generally results in a reduction of overall toxicity since less compound is generally required. Thus, in the case of analgesics, morphine and related opiates exhibit deleterious side effects such as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting and alterations in the endocrine and autonomic nervous systems. Opiate antagonists in the prior art have been reported to show as side effects endocrine and gastrointestinal disturbance. The novel compounds of the present invention are improved over prior art opiate compounds in potency and selectivity as opioid receptor agonists and antagonists and in reducing or being substantially free of reported side effects of prior art opiate compounds.
Some of the prior art compounds which have been associated with mu or delta agonist activity have demonstrated analgesic activity. The primary drawback with these prior art compounds when used as opioid analgesics is the respiratory depression as documented in Holiday, J. W. Current Concepts Scope Publications, Upjohn, Kalamazoo, Mi., 1985. On the other hand, opioid agonists prepared by Von Voigtlander, Journal of Pharmacol. Exp. Therap. 224: 7-12, 1983, have been shown to be selective to kappa - type opioid receptors which are suitable as analgesics with the advantage that they do not produce respiratory depression at analgesic doses.
Considerable evidence from radioligand binding studies in the prior art supports the existence of mu, delta, kappa and sigma opioid receptors [Simone et al. and in Opioids-Past, Present and Future, Tylor and Francis, London, pp 33-52, (1984) and Martin et al. J. Pharmacol. Exp. Therap. 196, 66 (1976)]. The mu-receptor was originally believed to be involved in the production of both analgesic and respiratory depressant effects. A more recent study suggests that one subclass of that receptor (mu.sub.1) is responsible for the former and the other (mu.sub.2) for the latter [Spiegel et al. J. Pharmacol. Exp. Therap. 228, 414 (1984)]. Subsequently the original group of investigators (Simone et al. Life Sci. in press (1985)) reported inhibition of overnight feeding by a mu.sub.1 -selective antagonist, naloxonazine.
The novel compounds of the present invention were the product of an extensive research investigation into the possible relationship between the hydrophobic bonding region present in the vicinity of the C-6 position of the opiate molecule when bound to the mu-receptor. The existence of the hydrophobic bonding region was clearly demonstrated by Pasternak et al. J. Med. Chem. 23, 674 (1980) in studies using the dimeric azines and the phenyl-hydrazones (Hahn et al. J. Pharmacol. Exp. Therap. in press (1985)). The ease of formation of oximes in the 14-hydroxy dihydromorphinone series has been the subject of a number of prior art references the most pertinent of which are believed to be Lewenstein et al. U.S. Pat. No. 3,320,262; Sawa et al. Tetrahedron, 24, 6185 (1968); Ko et al. J. Med. Chem. 27, 1727 (1984). The two known groups of oximes tested in the past were esters of carboxymethyl oximes [Lowenstein et al. U.S. Pat. No. 3,320,262] and oximes and their O-methyl ethers of oxymorphone, naloxone and naltrexone [Ko et al. J. Med. Chem. 27, 1727, (1984)].
In U.S. Pat. No. 3,320,262 only one compound, N-cyclopropylmethyl-nor-14-hydroxydihydrocodeinone-6-carboxymethyl methyl ester was examined in morphine dependent monkeys. At dosages of 1 and 2 mg/kg of body weight only, "partial suppression of symptoms was obtained" (Col. 6, ls. 67-71 of the patent). In the Ko et al. study the oximes and their O-methyl ethers of oxymorphone, naloxone and naltrexone were reported as less potent than parent ketones.
The unusually high potency and selectivity exhibited by the novel compounds of the invention is not disclosed or suggested in the available prior art. The novel and unexpected advantages of the potent selective opioid receptor agonists and antagonists over the prior art are further illustrated in the accompanying drawings together with the summary of the invention.
SUMMARY OF THE INVENTION
The present invention provides a potent, selective opioid receptor agonist or antagonist having the general formula: ##STR2## wherein R is cyclopropylmethyl, allyl or methyl, and R.sub.1 is an unsubstituted or substituted aryl, aralkyl, heteroaryl, heteroaralkyl or a cycloalkyl group, with or without a heteroatom like S,O,N; and the pharmaceutically acceptable salts thereof.